Multimodal Assessment of Pituitary and Parasellar Lesions

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Chapter 16 Multimodal Assessment of Pituitary and Parasellar Lesions

T. Brooks Vaughan, Lewis S. Blevins, Michael S. Vaphiades, Gary S. Wand

Pituitary and parasellar lesions represent a unique variety of neoplasms and other disease processes that are best addressed employing a multidisciplinary approach to assessment and treatment. Their close proximity to critical structures, potential association with endocrine dysfunction, and their propensity for recurrence or persistence after initial therapy often demands the skills of an experienced neurosurgeon, endocrinologist, radiologist, ophthalmologist, and radiation oncologist. Further, multiple tools, including laboratory tests, radiologic studies, and other specialized investigations are indispensable aids to patient care. This chapter will emphasize the need for a multimodal initial evaluation and a team approach to assessment.

Background and Epidemiology

The most common lesion encountered in the sella will be a pituitary adenoma. Estimates of the prevalence of pituitary adenomas vary widely between studies, which are performed using either MRI or autopsy findings. A recent meta-analysis found a prevalence of 22.5% in imaging studies (range 1%–40%) and 14.4% in postmortem studies (range 1%–35%), for an overall prevalence of 16.7%.¹ The vast majority of pituitary adenomas are microadenomas (diameter <1 cm). Macroadenomas are far less common, and their prevalence in the population is estimated to be approximately 0.2%.¹ Macroadenomas make up a much larger proportion of adenomas that come to clinical attention, however. A cross-sectional study of 81,149 patients in Banbury, UK found the overall prevalence of known pituitary tumors to be 77.6 cases per 100,000 inhabitants (or 63 total cases). Of these, only 7 were found incidentally. The others presented with some sort of clinical symptomatology, and of those, 41% were macroadenomas.²

The prevalence of “functional tumors”—adenomas that hypersecrete hormones resulting in a clinical syndrome—is in the range of 50% to 60% of all clinically apparent pituitary tumors. The most common functional or secretory tumors are prolactinomas (approximately 40%), followed by ACTH-secreting tumors (14%), growth hormone (GH)–secreting tumors (5%), and TSH-secreting tumors and mixed tumors (both under 1%).³ Many “nonfunctional” tumors are clinically silent gonadotroph adenomas, while a small proportion of these produce but do not secrete ACTH, GH, or TSH.

The majority of pituitary tumors remain stable after their initial detection. In one meta-analysis of eight studies including 144 patients who were followed from 2 to 8 years, 84% of microadenomas of the pituitary gland remained stable in size. A few (6%) regressed and approximately 10% increased in size. In contrast, 20% of macroadenomas grew (11% of those were due to apoplexy), 11% diminished in size, and 69% remained stable.⁴

Pathogenesis

A great deal has been learned about the pathogenesis of some pituitary lesions but the pathogenesis of the majority of pituitary and parasellar lesions is still unknown. It is clear there are a variety of molecular mechanisms responsible for neoplastic transformation. Pituitary adenomas arise from adenohypophysial cells of the anterior pituitary. The vast majority of pituitary tumors are thought to be benign. Adenomas can, however invade local structures including the dura of the sella, local bony structures, and the sphenoid sinus cavity. Pituitary carcinoma, defined by the presence of local discontinuous or systemic spread, is extremely rare and probably represents approximately 0.2% to 0.5% of all pituitary lesions.⁵ Pituitary neoplasms are monoclonal, and outside of defined genetic syndromes, their cause is not well understood.

At least five genes have been identified as causes of pituitary adenomas with four of them comprising familial pituitary tumor syndromes: MEN1, PRKAR1A, CDKN1B, and AIP. Genetic disorders such as MEN1 (a mutation in the MENIN protein that reverses function of tumor suppressor gene), and Carney’s complex (PRKAR1A, insufficient activity of protein kinase-A regulatory subunit 1) are examples of models for pituitary tumor development. The CDKN1B gene causes a MEN-like syndrome (MEN4) associated with hyperparathyroidism and other rare tumors.⁶ Another recently discovered mutation is located in the AIP (aryl hydrocarbon receptor–interacting protein) gene (11q13).^7,⁸ This appears to act as a tumor suppressor gene and mutations predispose to GH-secreting pituitary tumors.^7,^9,¹⁰ Approximately 40% of sporadic GH-secreting adenomas are associated with a somatic mutation in the Gs alpha gene.^11,¹² The mutation results in constitutive activation of the cAMP/PKA signal transduction pathway and leads to neoplastic transformation of somatotroph cells of the pituitary.^13,¹⁴

Clinical Presentation

Pituitary and parasellar lesions may come to attention in a variety of ways. They may be detected incidentally on radiographic scans obtained for unrelated reasons, or as a result of clinical symptoms and signs attributable to either endocrine dysfunction or to mass effect. Clinical syndromes of hormone excess result from hypersecretion of prolactin, growth hormone, ACTH or TSH causing the amenorrhea/galactorrhea syndrome, acromegaly, Cushing’s disease, or secondary hyperthyroidism, respectively. Rarely, patients have clinical features of gonadotropin excess. Mass effect symptoms and signs may include headache, visual field loss, diplopia, facial pain, and epistaxis, as well as CSF leaks. Further, varying degrees of hypopituitarism due to compressive injury may result in partial or complete loss of pituitary function. Thus, careful hormonal, neuroradiologic, and ophthalmologic assessments are essential in the evaluation of patients affected by these tumors.

The Initial Evaluation

The initial evaluation of patients with pituitary tumors begins with a general history and physical examination in order to determine if there are co-morbidities or other medical issues that will affect the evaluation and management of the pituitary patient. Surgical risk is determined and appropriate consultations are obtained when necessary. For example, patients with acromegaly and sleep apnea may require evaluation by a pulmonologist prior to surgery. Diabetes and hypertension in acromegalic and Cushingoid patients may require treatment to decrease surgical morbidity. A thorough assessment of the clinical manifestations of the disease process may guide the selection of subsequent laboratory and radiological studies. Laboratory assessment of the hormonal status of affected patients allows for determination of a specific diagnosis, subsequent treatment planning, and permits decisions as to whether or not hormone replacements are necessary.

Laboratory Investigations

The most appropriate screening tests for an incidentally discovered pituitary lesion are the topic of much debate.^15,¹⁶ A survey of endocrinologists in the United States and United Kingdom suggested that, when confronted with a microadenoma, a range of 0 to 16 tests would be ordered (median 7).^16,¹⁷ Most experts would advocate screening for both pituitary insufficiency and hormone excess as both states are relevant in the initial decision-making and also the long term follow-up of patients. This information is particularly important in the context of a preoperative evaluation. Clinical findings should guide medical decision-making. For example, patients who are obviously Cushingoid will require specific testing of adrenal function that may not be conducted in those who appear to have acromegaly.

Hypopituitarism

One or more pituitary deficiencies will be present in 70% to 90% of patients with macroadenomas.¹⁸ Microadenomas rarely cause pituitary insufficiency. Other tumors in the area of the sella, including tuberculum sellae and cavernous sinus meningiomas, craniopharyngiomas, and Rathke’s cleft cysts may also cause pituitary insufficiency. A uniform approach to screening for pituitary dysfunction is useful since symptoms and signs can be vague as many patients have adapted over time to a state of chronic pituitary dysfunction and may not perceive their symptoms as abnormal. Pituitary deficiency tends to manifest in the following order of frequency: loss of GH, followed by gonadotrophins, followed by loss of adrenal and then thyroid function.⁴ Diabetes insipidus is the least common deficiency in a typical pituitary adenoma. A typical screening panel therefore will include the following, with interpretation discussed below: serum IGF-1, estradiol, or testosterone levels (depending on sex) in conjunction with an FSH and LH level, TSH and free T4, and a cortisol stimulation test. A prolactin level should always be drawn as well and is discussed in the section on pituitary hypersecretion. Table 16-1 summarizes typical signs and symptoms of pituitary insufficiency.

Table 16-1 Signs and Symptoms of Pituitary Deficiency

Oral regimens for adrenal hormone replacement in a non-stressed patient include hydrocortisone 15 to 30 mg daily, usually in divided doses, dexamethasone 0.25 mg at bedtime, or prednisone 5 mg daily.²² Adjustments in dosing are based on clinical symptoms and signs of either glucocorticoid excess or deficiency, as there is, at this point, no reliable, reproducible laboratory test to assess the adequacy of treatment. The HPA axis is usually reassessed 6 to 8 weeks after surgery to determine if ongoing chronic treatment is necessary. Many patients will experience improvement in pituitary function after surgery and their glucocorticoid replacement may be abruptly discontinued. Patients with Cushing’s disease may experience a period of temporary adrenal insufficiency of 6 to 18 months due to suppression of normal corticotroph cells by pre-existing hypercortisolism. They must be reassessed at regular intervals to determine the need for ongoing steroid replacement.

Treatment with replacement doses of glucocorticoids is indicated in all patients with documented central adrenal insufficiency. Empiric treatment prior to surgery is acceptable in the setting of pituitary apoplexy, especially in the setting of large space occupying lesions, and when an urgent or emergent procedure is indicated even in the absence of documented adrenal dysfunction. A reasonable therapeutic regimen when the patient is under significant physiological stress is 25 mg of intravenous hydrocortisone every 8 hours. In a crisis, one may want to initiate intravenous glucocorticoid replacement with 100 mg initially and 50 mg every 8 hours thereafter. Mineralocorticoid replacement is not necessary in secondary adrenal insufficiency.²³

Diabetes Insipidus

Diabetes insipidus (DI), due to arginine-vasopressin (AVP) deficiency, is uncommon in pituitary adenomas. If present on the initial evaluation, consideration should be given to alternative diagnoses such as infiltrative lesions (hypophysitis, sacrcoidosis), metastatic lesions, craniopharyngiomas and other tumors. Cardinal features of DI include polyuria (more than 30 ml of urine per kilogram of body weight in 24 hr) in the presence of hyperosmolality, inappropriately dilute urine, dehydration, and subsequent thirst. When obtaining a history, it is helpful to inquire specifically about nocturnal symptoms, since many normal patients may perceive what they feel is excessive thirst or urination during the day. If their symptoms resolve overnight DI is unlikely. If DI is noted preoperatively, patients will require very close monitoring of fluid intake and urine output along with serum sodium levels.

Pituitary Hypersecretion

Pituitary adenomas can secrete hormones in excess resulting in particular clinical syndromes. Other sellar and parasellar tumors will not present in this fashion, although mild prolactin elevations can be seen with many large tumors due to compression of the infundibulum. The major hypersecretory states are discussed individually in other chapters, but all should be considered in the initial evaluation of a pituitary mass. Table 16-2 summarizes some of the possible signs and symptoms associated with various hypersecretory states.

Table 16-2 Signs and Symptoms of Pituitary Excess

Prolactinoma

Prolactinomas represent approximately 40% of pituitary tumors.¹ They are more common in women with a gender ratio of 10:1.²⁴ Women usually present when their tumors are microadenomas. Men are more likely to present with macroadenomas. Whether this is function of delayed presentation (women may present quickly with menstrual irregularities) or of unique biological properties of tumors in men is unclear.²⁵

A serum prolactin should be obtained in all patients with pituitary tumors, as this information will affect treatment decisions. Prolactin levels of greater than 200 μg/l are almost always associated with a prolactin-secreting macroadenoma. Prolactin levels less than 200 μg/l can be caused by microprolactinomas and also a variety of parasellar lesions (pseudoprolactinoma), infiltrative processes, as well as physiologic and pharmacologic causes.²⁴ Any tumor or infiltrative process that interferes with the delivery of dopamine, which inhibits prolactin production, to the normal lactotrophs can cause hyperprolactinemia that is often referred to as “stalk-effect hyperprolactinemia.” Pregnancy should be excluded in any woman with hyperprolactinemia and amenorrhea. A variety of drugs can cause hyperprolactinemia. If medications are suspected as a cause of hyperprolactinemia, they should be discontinued if possible, and the prolactin level reevaluated 1 month thereafter. Severe primary hypothyroidism can cause hyperprolactinemia. Thus, a serum TSH level is valuable during an initial evaluation of hyperprolactinemic patients.

The clinician must be aware that the differential diagnosis for hyperprolactinemia is large encompassing pathological and physiological causes. Defining the cause of hyperprolactinemia is crucial since true prolactinomas are treated medically with dopamine agonists, pseudo-prolactinomas are surgically removed and other causes have their own unique treatments. Table 16-3 presents a summary of the differential diagnosis of hyperprolactinemia.

Table 16-3 Differential Diagnosis of Hyperprolactinemia

Physiologic

Pathologic

Prolactinomas: micro- and macro-adenomas

Subset of growth hormone–secreting adenomas

Miscellaneous causes

Hypothyroidism

Idiopathic

Chronic renal failure

Chronic liver failure

Polycystic ovarian syndrome

Elevation without Clinical Symptomatology

Macroprolactinemia

Medications

Antihypertensives (methyldopa, reserpine, verapamil)

Antipsychotics (phenothiazines, butyrophenonones)

Antidepressants (tricyclics, occasional reports with SSRIs)

GI medications (metoclopromide, domperidone)

Narcotics

Estrogens

Protease inhibitors

Effects on the Pituitary Stalk

Mass effect from any sellar mass

Infiltrative disease (Histiocytosis, sacrcoidosis, metatasis, tuberculosis)

Sectioning of stalk from basal skull fracture, iatrogenenic surgical injury, facial trauma

Neurogenic

Chest wall injury

Chest wall lesion

Source: Adapted from Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am. 2008;37:67-99, viii.

A small subset of extremely large prolactinomas can produce enormous amounts of prolactin that overwhelm antibodies used in the assay resulting in a false lowering of prolactin levels.²⁶ This is known as the “hook effect.” In the setting of a macroadenoma, when a prolactinoma is suspected, prolactin levels should be performed on diluted serum samples to avoid this error in laboratory diagnosis. Most modern radioimmunoassays are able to detect prolactin levels as great as 4000 μg/l without being subject to the “hook effect.” We recommend that treating physicians being aware of the prolactin test performance in the laboratories they employ to evaluate their patients.²⁷

On occasion a patient will be found to have an elevated prolactin but without symptoms of hyperprolactinemia. This is often due to a condition known as macroprolactinemia. In this disorder, prolactin aggregates with circulating IgG antibodies resulting in decreased clearance of the complex and thus elevated prolactin levels.²⁸^–³⁰ However, the prolactin-IgG complex is devoid of biological activity and thus the absence of symptoms. This condition does not require treatment and needs to be distinguished from true hyperprolactinemia. Incubating the serum with polyethylene glycol, which removes the prolactin-IgG complex prior to performing the assay, can identify the phenomenon.

Cushing’s Disease

Cushing’s disease is a term applied to a specific form of Cushing’s syndrome (pathological hypercortisolism) caused by an ACTH-secreting pituitary tumor. Cushing’s syndrome may be due to a variety of other disorders including the syndrome of ectopic ACTH secretion, adrenal tumors, and exogenous glucocorticoid therapy for non-endocrine disease processes. Due to the risks that hypercortisolism can pose in the perioperative period, including deep venous thrombosis, pneumocystis pneumonia and other infections, poor wound healing as well as steroid hormone withdrawal in the postoperative period, most would have a low threshold to screen for Cushing’s prior to pituitary surgery.

Recent guidelines review proposed diagnostic approaches to the evaluation of patients with suspected Cushing’s syndrome.³¹ The inclusion of an endocrinologist experienced with this disorder to establish and confirm the diagnosis is strongly advised. Generally speaking, and depending on the clinical situation, one should start with screening tests, then proceed to diagnostic or confirmatory tests, and finally, to differential diagnostic tests.

There are at least three reliable screening tests to evaluate patients with suspected hypercortisolism. Keep in mind that screening tests are designed to be sensitive but not specific. Thus, there will be false positive tests and not everyone with a positive screening test will be ultimately diagnosed with pathologic hypercortisolism. Appropriate screening tests include the overnight 1 mg dexamethasone suppression test, the 24-hour urine collection for free cortisol and creatinine, and the midnight salivary cortisol collection.³²^–³⁶ For most patients who require screening only, performance of one of these tests is indicated. The salivary cortisol and 24-hour urine free cortisol collection should be done at least twice to confirm abnormal initial findings. A positive dexamethasone suppression test is identified when an 8 a.m. cortisol is greater than 1.8 μg/dl following administration of 1 mg of dexamethasone at 11 p.m. the prior night. Using this cutoff gives the test a sensitivity of approximately 95% with specificity of 80%. To enhance specificity to over 95%, a cutoff of 5 μg/dl may be used, which will sacrifice sensitivity (falling to 85%).³¹ A 24-hour urine cortisol above the upper limits of normal may be considered a positive screening test, along with a late-night salivary cortisol level of 4 nmol/l or greater.³¹

Diagnostic tests are designed to balance sensitivity and specificity. They are used to confirm the diagnosis of pathologic hypercortisolism. Diagnostic tests for hypercortisolism include the 24-hour urine cortisol, the dexamethasone suppressed CRH stimulation test, (CRH/Dex test) and the formal low-dose dexamethasone suppression test.^37,³⁸ A 24-hour urine cortisol excretion rates greater than two to three times the upper limit of normal is generally considered to be a positive test. The CRH/Dex test is performed by administering dexamethasone, 0.5 mg every 6 hours for 2 days followed by CRH stimulation on the morning of the third day. A cortisol value greater than 1.4 μg/dl 15 minutes after CRH administration indicates an abnormal result.³⁹ Treating physicians are encouraged to review the performance of tests employed by their laboratory and draw upon their own experiences to determine what constitutes an abnormal response to a formal dexamethasone suppression test.

Once Cushing’s syndrome is established, the cause must be identified: ACTH-secreting pituitary adenoma (Cushing’s disease), ectopic ACTH production or an adrenal tumor. Differential diagnostic tests for hypercortisolism include the plasma ACTH level, the overnight high-dose dexamethasone suppression test, and inferior petrosal sinus sampling. The first step in identifying the cause of Cushing’s syndrome is to obtain a random ACTH level and perform a high-dose dexamethasone test. If the plasma ACTH levels are low (levels depend upon the assay employed), then an ACTH-secreting tumor is ruled out. If ACTH levels are normal or elevated the result indicates that Cushing’s syndrome could be secondary to a pituitary tumor or ectopic production of ACTH by tumors located below the neck.

The high-dose dexamethasone suppression test is often, but not always useful in distinguishing these two entities. Generally cortisol levels do not suppress substantially when the cause of the Cushing’s is an ectopic tumor; however there are many exceptions. On the other hand, cortisol levels in the setting of an ACTH-secreting adenoma generally suppress by greater than 50% from baseline values. When the suppression does not approach or exceed 90%, or when the results are difficult to interpret, inferior petrosal sinus sampling is indicated. Patients thought to have Cushing’s disease should undergo an MRI scan of the pituitary gland.

Inferior Petrosal Sinus Sampling

Inferior petrosal sinus sampling is a procedure that may be required to confirm the source of ACTH-dependent Cushing’s syndrome. Lab studies can often differentiate ectopic from pituitary ACTH-driven Cushing’s syndrome, but it is clear that the levels, even on dynamic testing, may have some overlap. IPSS may be particularly useful when the lab evaluation suggests a pituitary source for ACTH but none can be identified by MRI scanning. Studies have varied in their estimation of the sensitivity and specificity of the test. Earlier studies have shown it to be very sensitive (96%) and specific (100%), but there have been recent studies questioning these estimates.^40,⁴¹ It is clear that the experience of the practitioner has an effect on the utility of the test, and even some large medical centers may not be able to perform the procedure reliably.

The technique is performed by cannulation of the bilateral femoral veins, and advancing catheters into the inferior petrosal sinuses via the internal jugular veins. Baseline ACTH values are obtained from the periphery and the inferior petrosal sinuses both before and after CRH stimulation (1 μg/kg of body weight). A ratio of 2.0 from the petrosal sinus to the periphery before CRH stimulation, or 3.0 afterward is felt to be consistent with pituitary Cushing’s disease. In ectopic disease, the ratio is typically less than 2.0 both before and after CRH stimulation.⁴²

False negative tests have been described in several situations. Ectopic pituitary tumors can render it inaccurate, as can hypoplastic or anomalous inferior petrosal sinuses. While IPSS results can lateralize, those findings may be misleading and are not highly specific. One study suggested that a gradient of 1.4 across sides was able to predict tumor location 78% of the time.⁴²

Acromegaly

Growth hormone–secreting pituitary tumors account for 95% of acromegaly. Rarely, ectopic GH- or GH-releasing-hormone (GHRH)–secreting tumors are a cause. Most pituitary tumors are macroadenomas at the time of diagnosis. Approximately one third of tumors secrete additional pituitary hormones such as prolactin or TSH.⁴³

In most patients, screening with an IGF-1 level is sufficient to establish the diagnosis. IGF-1 levels are reported as age-adjusted and attention should be paid to where the level falls within the normal range. When the IGF-1 levels are slightly elevated, an oral glucose suppression test is indicated. This test is performed by the oral administration of 75 grams of glucose and the measurement of serum GH levels every 30 minutes for 2 hours. Using the modern ultrasensitive assay, a normal individual will suppress GH levels to below 1 μg/l.⁴⁴

Hyperthyroidism

TSH-secreting adenomas are uncommon and account for less than 1% of all pituitary adenomas. These aggressive tumors usually present as macroadenomas with a goiter and clinical features of hyperthyroidism. Generally, the free T4 and T3 levels are elevated in the setting of an inappropriately normal or elevated serum TSH concentration. TSH-secreting tumors often co-secrete other hormones; therefore measurement of PRL, GH and alpha subunit should be performed.^45,⁴⁶ The alpha subunit can be useful in distinguishing TSH-secreting pituitary adenomas from thyroid hormone resistance (either pituitary, peripheral or generalized types). A suggested method to confirm the presence of a TSH-secreting tumor is to calculate the molar ratio of alpha subunit to TSH: (alpha subunit in nmol/l)/(serum TSH in μIU/l) × 10. A ratio exceeding 1.0 is found in 80% of patients with TSH-secreting adenomas.⁴⁵ Preoperative control of the hyperthyroidism is necessary and can be achieved with somatostatin analogs or the brief use of antithyroid medication, possibly in combination with beta-blockade.

Radiologic Studies

The differential diagnosis of sellar and parasellar neoplasms is quite large (Table 16-4). In many cases, an accurate diagnosis may be arrived at based on clinical symptoms and signs, and specific radiographic features. Occasionally, however, sellar lesions mimic one another and the actual diagnosis may only be resolved by histologic examination of resected tissue. Magnetic resonance imaging (MRI) is the primary modality employed in imaging of sellar and parasellar neoplasms. A typical MRI protocol calls for sagittal and coronal imaging, with thin-sectioned (2-3 mm) T1-weighted images with and without contrast. Some disease processes have very well defined characteristics on MRI that permit their identification prior to surgery. Computed tomography has a role in the evaluation for calcifications within the lesion and in defining the integrity of the parasellar bony anatomy. It may also be acutely useful in suspected apoplexy to identify hemorrhage.

Table 16-4 Lesions of Sella and Parasellar Region

Type of Lesion	MRI/CT Findings	Clinical Clues
Physiologic enlargement of the pituitary	Larger than average gland without discrete tumor seen	Pregnancy, primary hypothyroidism, hypogonadism and adrenal insufficiency, normal variant May return to normal size after underlying endocrine cause is treated/resolves

Pituitary microadenoma Hypointense lesion when compared to normal gland on postcontrast T1 images Pituitary insufficiency rare. May be nonsecretory or secrete prolactin, ACTH, GH, or very rarely TSH Pituitary macroadenoma May see sellar expansion, deviation of the stalk away from the tumor, elevation of optic chiasm, occasional invasion into cavernous sinuses, sphenoid sinuses, suprasellar cistern or pterygopalatine fossa Pituitary insufficiency common in non-secretory lesion. May secret prolactin, ACTH, GH or rarely TSH. Multiple hormones can be secreted, and insufficiency of some hormones may accompany excess of others Pituitary apoplexy CT scan may be initially useful revealing hemorrhage. Hemorrhage initially hyperintense on T1 images, hypointense on T2. Eventually hyperintense on both types of images Sudden headache, signs and symptoms of acute central adrenal insufficiency, cranial nerve palsy, visual compromise

Cystic pituitary lesions:

Rathke’s cleft cysts

Pars intermedia cysts

Arachnoid cysts

Cyst fluid often dark on T1 imaging and bright on T2 imaging, but if fluid is proteinaceous, can be dark on both. Arachnoid cysts usually suprasellar, but can be intrasellar and displace gland posteriorly Headaches, pituitary insufficiency possible Empty sella Small gland may be present on floor of sella. “Sword sign” seen as stalk transverses empty sella Pituitary insufficiency possible, but function usually normal Craniopharyngioma Cystic lesion. Calcification on CT high specific, not sensitive. Can be cystic, solid, or both. Solid component may be bright on T1, cystic component bright on T2 Diabetes insipidus, pituitary insufficiency common. More common than pituitary adenoma in children Meningioma Uniform appearance on CT and MRI with similar appearance to gray matter. May lateralize within sella. Tuberculum sellae meningioma may have tail (“bird’s beak”). May encase vessels and narrow lumen Lateralizing visual symptoms Chordomas/chondrosarcomas May be calcified on CT. May be quite invasive. May destroy rather than expand sella Visual symptoms most likely complaint. Pituitary insufficiency rare Gliomas May arise from optic tract or nerves. May be hypointense on T1 images and hyperintense on T2.

Visual symptoms most likely complaint

Pituitary insufficiency rare

Germ-cell tumors (teratomas, germinomas, choriocarcinomas) Enhance with CT contrast, isointense to brain on T1 images, hyperintense on T2 Most common in children and adolescents. DI and pituitary insufficiency common CNS lymphomas Contrast enhancing, contact subarachnoid space, can be necrotic Possibly in context of disseminated lymphoma and immunocompromise. Can be seen as sole lesion and in immunocompetent Inflammatory/infectious lesions Thickening of stalk, loss of posterior pituitary bright spot

Diabetes insipidus common along with other pituitary deficiencies

Evaluate for signs and symptoms of TB, sacrcoidosis, Wegener’s granulomatosis, histiocytosis

Vascular lesions Black on MRI, homogeneous blush on contrast CT. MRA diagnostic

Source: Adapted from Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB. Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab. 2005;90:3089-3099.

Pituitary Hyperplasia

The normal pituitary gland is 9 to 10 mm in greatest dimension. It is rectangular on coronal section and somewhat semilunar on sagittal section. Physiologic enlargement of the pituitary gland, as can be seen in young menstruant women, and hyperplasia that can be seen during pregnancy, in the setting of primary hypothyroidism, primary adrenal insufficiency, or hypogonadism, can lead to a trapezoidal shape of the gland on coronal sections and a globular shape on sagittal sections. These entities should be considered prior to assuming that pituitary enlargement represents a pituitary tumor.^4,⁴⁷

Pituitary Adenomas

Microadenomas of the pituitary gland typically show diminished enhancement on postcontrast T1 images through the sella. The normal pituitary will appear hyperintense in relationship to the tumor. The pituitary stalk will often deviate laterally towards the contralateral side from the tumor on coronal imaging. Occasionally, however, postcontrasted images fail to delineate the tumor. In this setting, and when there is obvious evidence for a syndrome of hormone hypersecretion, serial dynamic contrast-enhanced images often delineate a microadenoma. Macroadenomas of the gland are obvious. On occasion, these lesions are hypodense. The normal pituitary is often displaced laterally or superiorly and will enhance. Occasionally, tumors invade the cavernous sinuses or extend inferiorly into the sphenoid sinuses, inferiorly and laterally into the pterygopalatine fossa and related spaces, or extend superiorly into the suprasellar cistern and elevate the optic chiasm. Magnetic resonance imaging provides for excellent definition of the limits of growth of a pituitary macroadenoma in most cases.

The syndrome of pituitary apoplexy can result from either hemorrhage or infarction of a pre-existing pituitary tumor. It has some unique presenting characteristics that are quite different from other pathology in the region. Early during the initial event, CT may be helpful, but if not directed at the sella details may be missed. MRI of the hemorrhage in the first few days will be hyperintense on T1 weighted imaging and hypointense on T2. As time progresses, hemorrhage will be hyperintense on T1 and T2 weighted imaging as hemoglobin degrades to methemoglobin, and fluid levels may begin to be seen as sedimentation begins. In the case of visual loss, more rapid surgical intervention may lead to better outcomes.⁴⁸

Pituitary Cystic Lesions

Some pituitary adenomas undergo degenerative change and may present as predominately cystic or solid and cystic lesions within the sella. The cyst fluid is usually hypointense on T1 images with or without contrast. Cystic adenomas may be hyperintense on T2 imaging. Occasionally, hemorrhage is seen within pituitary tumors. Blood products are usually hyperintense on T1 images. Primary pituitary cysts, such as pars intermedia cysts and Rathke’s cleft cysts are usually hypointense on T1 imaging. The latter lesions, however, may mimic a pituitary tumor. These lesions may not be hyperintense on T2 imaging if the fluid is very proteinaceous. Arachnoid cysts are most commonly suprasellar, but can be intrasellar and are often hypointense and distort the sellar contents and displace the pituitary stalk posteriorly.^47,⁴⁹ Patients who have primary or secondary empty sella often have a small gland, usually situated in the floor of the sella, and the pituitary stalk traverses the empty sella as it passes to the residual or remnant gland. In many patients, the stalk is straight and tapered and has the appearance of a sword leading to the well known “sword sign” taken to confirm the presence of an empty sella and exclude the diagnosis of an intrasellar cyst.

Craniopharyngiomas

Craniopharyngiomas are epithelial tumors that arise along the path of the craniopharyngeal duct. They are the most common lesions of the parasellar area in children. There is a bimodal age distribution, with peak prevalence seen in children 5 to 14 years old and adults 50 to 74 years old.⁵⁰ They can have imaging characteristics in common with cystic pituitary lesions. CT scanning may be useful when a craniopharyngioma is suspected, and the presence of calcium within the lesion on CT is highly suggestive, but is only seen in 50% of such tumors. The tumors may be solid, cystic, or both. The solid component will often enhance with contrast on T1 weighted MRI imaging and the cystic component will usually be hyperintense on T2 weighted imaging.⁵¹ Craniopharyngiomas may also be located in the region of the pituitary stalk or situated with an epicenter in the hypothalamus. The majority will be between 2 and 4 cm in diameter, but they can be bigger.⁵⁰ Suprasellar craniopharyngiomas may result in mass effect on the ventricular system and are often accompanied by a high rate of hypopituitarism and diabetes insipidus.

Meningiomas

Meningiomas are usually benign neoplasms of the dura mater. The majority are WHO grade I, but atypical (WHO II) and anaplastic (WHO III) lesions are described.⁵² Peak incidence is in the 4th to 7th decade.⁵³ In adults, they are the second most common lesion encountered in the parasellar area after pituitary adenomas.⁵⁴ Parasellar meningiomas include those that arise from the diaphragma sella, tuberculum sella, or the dura overlying the medial walls of the cavernous sinuses. They are often diagnosed based on imaging characteristics. They tend to have very uniform enhancement with gadolinium contrast and their appearance is similar to gray matter both on CT and MRI.⁴⁷ A gnarled appearance is often seen in cavernous sinus meningiomas. Tuberculum sellae meningiomas often have a dural tail that extends over the planum sphenoidale, which distinguishes them from pituitary adenomas.⁴⁹ On coronal sections, this tail often gives the appearance of a bird’s beak. Adjacent bone may be thickened or sclerotic. Meningiomas often encase arterial vessels and narrow their lumen, which is again atypical of pituitary adenomas.⁵¹

Chordomas and Chondrosarcomas

Chordomas and chondrosarcomas are cartilaginous tumors arising from the notochord remnant in the skull base. Chordomas are low-grade tumors, but can be quite destructive and have a significant mortality risk (5-year survival 65%).⁵⁵ Intracranial chondrosarcomas are far less common than chordomas and fewer than 200 are described in the literature.⁵⁶ These lesions grow in all directions and can efface normal anatomic structures, compress the brainstem, and obliterate the sella. They tend to invade and destroy the sella rather causing the expansion one may see with a typical pituitary adenoma. They often cause bony destruction and may contain calcifications best seen on CT. They tend to be hyperintense on T2 weighted imaging and enhance with contrast. Like craniopharyngiomas, these lesions may be calcified on CT scanning.

Initial presenting complaints are likely to be related to visual symptoms or headaches. Diplopia is more likely than visual field defects, reflecting their propensity to affect the cranial nerves within the cavernous sinuses.⁵¹ They are not likely to be associated with pituitary insufficiency, but it has been described, particularly in association with chondrosarcoma.⁵⁶

Other Malignant Lesions of the Sella

Parasellar gliomas, malignant lesions that can range from low to high grade, arise from glial tissue located in the hypothalamus, optic chiasm, optic nerves, or the optic tracts. Examples include pilocytic astrocytomas, a low-grade (WHO I) lesion, that is often associated with neurofibromatosis type 1 (NF-1). Higher-grade gliomas in the parasellar region include astrocytomas (WHO II) and anaplastic astrocytomas. Occasionally astrocytomas will progress to gliobastomas (WHO grades III-VI).⁵¹ These lesions tend to be large, potentially infiltrative, suprasellar masses. They tend to be hypointense to brain on T1- weighted images and hyperintense on T2 weighted images. They may demonstrate heterogeneous enhancement with contrast.⁵

Germ-cell tumors (germinomas, choriocarcinomas, teratomas) are most commonly seen in childhood and adolescence. There are often synchronous lesions located in the suprasellar region, the vicinity of the third ventricle, and in the area of the pineal gland. These lesions often are suspected based on the radiographic characteristics in conjunction with the clinical presentation characterized by profound hypopituitarism and diabetes insipidus. These lesions tend to enhance with CT contrast and be isointense to brain on T1-weighted images and hyperintense on T2-weighted images.

Primary CNS lymphomas in the parasellar region have been described in both immunocompromised and immunocompetent patients. Presenting features include including diabetes insipidus, pituitary stalk thickening, and fever.⁵⁷ Synchronous lesions are not uncommon and there may be evidence of disseminated lymphoma. Contrast-enhancing lesions in contact with the subarachnoid space and without necrosis are characteristic of parasellar lymphomas.

Metastases to the parasellar region may mimic a lesion of the pituitary stalk or of the sella. In most cases, there is additional evidence for intracranial metastases or distant metastases to other sites including the skeletal system and the liver. Melanoma and carcinomas of the breast and lung account for most cases of metastases to the pituitary stalk. Imaging characteristics may mimic a primary stalk tumor such as a glioma or choristoma or an infiltrative process causing thickening of the pituitary stalk.⁵ These tumors tend to have irregular borders.

Inflammatory Lesions

A variety of infiltrative and inflammatory lesions may affect the parasellar region. Many of these disorders will manifest in the context of systemic symptoms of the underlying disease process. While radiographic and clinical features may be pathognomonic, in many cases, a diagnosis of infiltrative disease is secured by a response to steroid or antibiotic therapy and in some cases, only after surgery has been performed and the biopsy evaluated.

Sarcoidosis may present as a sellar mass, as thickening of the pituitary stalk, or even as a hypothalamic mass. Some patients may have communicating hydrocephalus and leptomeningeal enhancement. The disorder may be limited to the central nervous system or may be seen in association with the typical pulmonary or skin findings of sarcoidosis. Hyperprolactinemia due to stalk effect, DI, and hypopituitarism are not uncommon. An elevated serum or CSF ACE level may be helpful in securing the diagnosis but biopsy is often required. The pituitary “bright spot” on T1 weighted imaging may not be seen in patients who have resultant diabetes insipidus. Sarcoid granulomata tend to be isointense on T1 weighted imaging and will often enhance with gadolinium.⁵⁸

Lymphocytic hypophysitis is characterized by either focal or diffuse infiltration of the pituitary by lymphocytes with accompanying inflammation and is felt to be an autoimmune disorder. Hypophysitis often mimics a pituitary tumor. The inflammatory mass is often diffuse and hyperintense on postcontrast T1 images. Patients usually have profound degrees of hypopituitarism that are not usually seen when similar degrees of enlargement of the sellar contents are seen in other disorders such as meningiomas, pituitary adenomas, and so on.⁴⁹ Lymphocytic neuroinfundibulohypophysitis is associated with diabetes insipidus and loss of the pituitary bright spot on MRI. Xanthomatous hypophysitis is described as a reaction to ruptured cyst components.⁵⁸ The appearance on MRI may be indistinguishable from sacrcoidosis, and clinical manifestations are similar.

Wegener’s granulomatosis may affect the pituitary and mimic an inflammatory condition. Most patients have evidence of coexisting renal and pulmonary disease. MRI often reveals a thickened infundibulum, but will not reliably distinguish this lesion from other inflammatory processes.⁵⁸

Langerhan’s cell histiocytosis is characterized by proliferation of specific dendritic cells of the reticuloendothelial tissue. This disorder is more common in children (70%) than it is in adults (30%) and is quite rare. Diabetes insipidus is one of the more common early manifestations of the disorder. A thickened pituitary stalk and lack of a posterior pituitary bright spot on MRI may be seen.⁵⁸ Occasionally patients also have lesions involving the skin, liver, lungs, spleen, and bone marrow.

Infectious Disorders

Pituitary abscesses may be seen in the setting of a pituitary tumor and are more common in the setting of a pre-existing Rathke’s cleft cyst. These infections may also be seen in patients with sphenoid sinusitis. On MRI, a pituitary abscess is typically cystic, hypo- or iso-intense on T1 weighted imaging and hyper or iso-intense on T2 imaging. Ring enhancement is often seen. Fever is not reliably present. Pituitary abscesses are often first diagnosed at the time of pituitary surgery when the surgeon encounters pus. Cultures should be obtained to permit appropriate identification of the infectious agent and directed antibiotic therapy.^59,⁶⁰

Intracranial tuberculosis is uncommon. The prevalence depends upon the underlying prevalence of tuberculosis in particular patient populations. Affected patients usually have systemic manifestation of the disease process but pituitary and suprasellar lesions have been described as the sole or presenting feature of the infection. A recent report illustrates a case where a tuberculoma was misdiagnosed as idiopathic granulomatous hypophysitis for which steroid treatment was initiated. The patient developed tuberculous meningitis, illustrating the need to maintain a degree of suspicion and to ensure antibiotic therapy is provided when indicated.⁶¹

Vascular Disorders

Intrasellar aneurysms arise from the carotid arteries but can arise from the anterior communicating arteries. These lesions often mimic pituitary adenomas but can usually be readily distinguished by appropriate imaging techniques. They may appear black on conventional MRI and show homogenous blush on contrasted CT images.⁵⁸ MRA or conventional angiogram may confirm the diagnosis, and should be considered if an aneurysm is suspected.

Ophthalmologic Studies

The ophthalmologic exam and associated testing is a critical component of the evaluation of the patient with a sellar or parasellar lesion. In many cases these patients may present with visual complaints that ultimately lead to the discovery of their lesion. An experienced neuro-opthalmologist can often discern a great deal about a tumor’s location and some clues about its etiology from a detailed exam. Alternatively, the lesion may be discovered by other means, and the ophthalmologic exam may reveal previously unknown visual symptomatology that may influence the treatment plan, particularly in regards to surgery.

The optic chiasm is typically few millimeters above the diaphragma sellae separated by the suprasellar cistern. However, the chiasm can occupy both a “prefixed” or “postfixed” relationship to the diaphragma sellae (each in about 5% of the population). In the prefixed position, the chiasm is placed more anteriorly, with a shorter length of the optic nerves traveling over the pituitary gland and any potential associated pathology. In the postfixed position, the chiasm is more posterior, and a longer section of optic nerve is above the gland. The position of the chiasm will produce differing clinical manifestations when compression occurs from below. Lateral to the pituitary gland cranial nerves III, IV, V₁, V₂, and VI traverse the cavernous sinus.⁶²

To review, the chiasm represents the junction the optic nerves. The temporal fibers come from each optic tract, do not cross the chiasm, and travel anteriorly to innervate the ipsilateral eye. The nasal fibers cross the chiasm and travel to the contralateral eye. Therefore visual information from the left visual space is transmitted to the right cerebral cortex, and information from the right visual space is transmitted to the left visual cortex. The nasal fibers are arranged such that the upper quadrant fibers remain superior and cross posteriorly in the chiasm. The lower quadrant fibers remain inferior, and cross anteriorly in the chiasm. Thus, visual findings may differ depending on whether compression comes from above or below the chiasm.

The first step for the examining neuro-ophthalmologist is a thorough history and physical exam. This will include the formal ophthalmologic testing discussed below, but also vital signs, investigation of the integrity of the cranial nerves, and attention to the overall physical appearance of the patient, who may exhibit signs or symptoms of an underlying endocrine disorder. The manner in which the symptoms presented (sudden vs. gradual) and the exact nature of the symptoms are critical. Patients may present with visual field loss and complaints related to bumping into objects or difficulties while driving. The loss may manifest itself simply as a subtraction of the visual field, not blackness, which is more suggestive of optic nerve or retinal pathology. Changes in color vision may be noted, along with headache, diplopia, or ptosis.

A thorough ophthalmologic examination is extremely important. This is performed preferably with the patient’s own corrective lenses, or if unavailable, with manifest refraction or correction by pinhole. Usually, in early chiasmal compression from a pituitary tumor, visual acuity and visual fields will be normal or near normal. Loss of visual acuity may suggest a very large pituitary tumor or pathology other than a typical pituitary lesion. Visual testing should also include color vision testing with pseudoisochromatic plates and formal visual field testing. Desaturation of color vision may be one of the earliest signs of a chiasmal lesion, preceding actual field deficits.⁶³

All patients suspected of having a visual problem should have confrontational field testing. However, in the ophthalmologist’s office, automated visual fields, usually by Humphrey automated perimetry, should be performed. This testing is critical, as it may be used as a baseline against which to compare future examinations and is often the first clue to the examining physician that the patient may have a pituitary tumor large enough to cause a visual field deficit. The most typical initial visual field defect associated with a pituitary adenoma is a bitemporal superior quadrantic defect, produced due to pressure from below on the chiasm. A bitemporal inferior quadrantic defect is suggestive of pressure from above, as might be seen from a craniopharyngioma growing downward onto the chiasm. More severe pressure from either direction can produce a dense bitemporal hemianopsia.^62,⁶³

The pattern of visual field deficit may vary depending upon whether the chiasm is prefixed, postfixed, or normal. Pressure upon a prefixed chiasm, especially if not exactly midline, may result in a homonymous hemianopia on the side contralateral to the tumor. A postfixed chiasm may allow for minimal visual loss despite a very large tumor, or may manifest with symptoms mimicking optic neuritis with pain on eye movement, monocular visual acuity loss, and a central scotoma on visual field testing. A Marcus-Gunn pupil or relative afferent pupillary defect (RAPD) is predicated upon inter-eye luminance disparity. Its presence indicates that the amount of illumination reaching the midbrain from each retina and optic nerves is unequal. It will appear to be a paradoxical dilation of the abnormal eye when viewing each eye as it is illuminated. An RAPD is an indication of more marked chiasmal compression and visual field loss.

Formal testing of ocular motility, including ductions, saccades, pursuit, and alternate cover tests may reveal pathology related to the compression of cavernous sinuses and CN III, IV, and VI. Pathology in this area should certainly lead to consideration of cavernous sinus extension of a pituitary tumor, but also to alternative pathology. Involvement of CN III may result in a unilateral dilated pupil, ptosis, and a globe that is deviated inferiorly and laterally. Involvement of CN IV will result in vertical diplopia and upward deviation. Involvement of CN VI will result in horizontal diplopia due to the inability to abduct the involved eye. It is likely that deficits will be seen in combination. Horner’s syndrome may develop due to compression of the sympathetic neurons in the cavernous sinus.^62,⁶³

The fundoscopic exam may provide clues as to the duration of the deficit. Papilledema is almost never seen in the setting of a pituitary lesion, but could result if the tumor blocks the foramina of Monro. More typically, optic atrophy may be seen, which is felt to take at least 4 to 6 weeks to develop. Retinal processes, which may at times mimic chiasmal disease, should be excluded, as well as optic disc anomalies.

It is important to form a differential diagnosis during the exam, which will typically be supplemented by MRI scanning, preferably of the brain and orbits with and without fat suppression and gadolinium. Chiasmal findings, which respect the midline, are suggestive of pituitary adenomas, suprasellar meningiomas or aneurysms, and craniopharyngiomas. Para-chiasmal findings suggest alternate pathology and potentially lateralization and may be seen with other tumors such as optic gliomas, or sphenoid wind meningiomas. Multiple cranial nerve involvement can exist in the presence of malignancy or apoplexy.

Coordination of Care

The diseases discussed in this chapter are uncommon and complex. Several studies illustrate that experienced pituitary neurosurgeons obtain greater likelihoods of surgical success and have lower rates of surgical morbidity and mortality.⁶⁴ Neuroradiologists play a key role in providing expert interpretation of radiographic images and in establishing a differential diagnosis. When indicated, neuro-ophthalmologists conduct in-depth evaluations to document whether pituitary and parasellar lesions have affected the visual pathways. Radiation oncologists are essential in the management of patients with residual tumors, and in particular those with residual hormone-secreting neoplasms.

Logistically, it is best if this evaluation can happen in a coordinated fashion in a single day. This is easiest in a dedicated pituitary clinic, but could be done in separate clinics with close communication between physicians. Due to the low prevalence of the diseases described in this chapter, patients are often forced to travel long distances to reach an experienced center. It is very helpful if there is a designated coordinator to ensure appropriate labs and images are conducted and available at the time of the visit. Treatment requires constant communication between physicians, often accomplished electronically. A periodic case conference where involved specialists can discuss challenging cases, jointly review imaging and pathology, and clarify treatment plans is extremely helpful. Much of the endocrine testing described above is highly technical, carries some risk, and is best accomplished in a dedicated infusion center.

Endocrinologists play an essential role in the evaluation and management of patients with pituitary tumors and related disorders. They are often called upon to coordinate the care amongst the subspecialists involved in the case. Endocrinologists conduct postoperative assessments of the adequacy of pituitary function and of the biochemical status of residual disease in patients with hormone-secreting neoplasms. Endocrinologists are essential in the medical management of persistent hormone hypersecretion and in the coordination of adjuvant therapy including reoperation and radiotherapy, adrenalectomy, and so on. In the event that an endocrinologist is unavailable, it behooves the treating neurosurgeon to play the role of assessor of the medical and endocrine status of the patient or to work with a designated primary care physician.

Key References

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Buchfelder M., Schlaffer S. Surgical treatment of pituitary tumours. Best Pract Res Clin Endocrinol Metab. Oct 2009;23(5):677-692.

Buurman H., Saeger W. Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. Eur J Endocrinol. May 2006;154(5):753-758.

Castro M., Elias P.C., Quidute A.R., et al. Out-patient screening for Cushing’s syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests. J Clin Endocrinol Metab. Mar 1999;84(3):878-882.

DiGiovanni R., Serra S., Ezzat S., Asa S.L. .A.I.P. Mutations are not identified in patients with sporadic pituitary adenomas. Endocr Pathol. Summer 2007;18(2):76-78.

Elston M., McDonald K., Clifton-Bligh R., Robinson B. Familial pituitary tumor syndromes. Nat Rev Endocrinol. Aug 2009;5(8):453-461.

Ezzat S., Asa S.L., Couldwell W.T., et al. The prevalence of pituitary adenomas: a systematic review. Cancer. Aug 1 2004;101(3):613-619.

Fernandez A., Karavitaki N., Wass J.A. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010;72:377-382.

FitzPatrick M., Tartaglino L.M., Hollander M.D., et al. Imaging of sellar and parasellar pathology. Radiol Clin North Am. Jan 1999;37(1):101-121. x